ES2885851T3 - Nutritional composition for use in stimulating liver maturation - Google Patents

Abstract

Synthetic nutritional composition that can be evacuated more quickly from the stomach after consumption in an individual, comprising, with respect to total fats: - intermediate chain fatty acids, at least 98% in the form of triglycerides, in an amount included in the range of 0% to 15% by weight, - at least one unsaturated fatty acid comprising oleic acid in an amount of at least 35% by weight, with respect to total fats, - palmitic acid, at least 98% in the form of triglycerides, in an amount within the range of no more than 13%, for use in stimulating liver maturation and/or for reducing the risk of liver disease.

Description

description

Nutritional composition for use in stimulating liver maturation

Technical field of the invention

The present invention relates to synthetic nutritional compositions for use in stimulating liver maturation and/or reducing the risk of liver disease. The compositions according to the invention have a low content of intermediate chain fatty acids (MCFA) and a low content of palmitic acid.

Background of the invention

Recovery from illness requires adequate nutrition, but critically ill patients may develop feeding intolerances. Health care providers typically discontinue enteral feeding and turn to parenteral feeding in order to provide the patient with the required nutrition.

However, parenteral nutrition is not without drawbacks. This increases the risk of catheter-associated infections and sepsis, liver disease, and other comorbidities. Feeding intolerance can also develop in vulnerable infants and/or young children, such as infants and/or toddlers who are low birth weight, critically ill, born premature, experiencing intrauterine growth retardation, and/or who suffered from stunted growth due to disease and/or malnutrition.

In the case of vulnerable infants, especially premature infants, feeding intolerance is essentially due to immaturity of the gastrointestinal tract. Immature gastrointestinal motility leads to slow transit, delayed gastric emptying, causing the bolus to accumulate in the stomach (ie gastric residuals) and preventing continuation of enteral nutrition. These infants also have particularly low levels of digestive enzymes and bile salts, as well as limited absorption capacity. As a consequence, digestion and absorption of nutrients, particularly that of fat, is suboptimal and a large proportion of nutrient intake and energy is lost in the faeces.

Document n0 EP2767175 refers to a liquid nutritional composition for the improvement of the intestinal barrier function comprising lipids with short-chain fatty acyl chains and non-digestible fermentable saccharides.

Document no EP1996031 relates to a method for feeding low birth weight infants (LBW infants), very low birth weight infants (VBIPa N), extremely low birth weight infants (PEBAN infants) and infants preterm infants to improve oral tolerance.

Liver function is immature in preterm infants, and liver dysfunction is common in preterm infants, affecting up to 50% of extremely low birth weight (ELBW) infants. Both premature infants and older patients receiving parenteral nutrition for more than a few weeks are at greatest risk for life-threatening hepatobiliary disorders, from cholestasis to end-stage liver disease.

Therefore, an improved nutritional composition that allows the convenient, safe and precise delivery of the most suitable nutrition is desired, in particular to patients who develop or are at risk of developing feeding intolerance, and in particular nutritional compositions would be advantageous. that avoid the risks of parenteral nutrition and/or that accelerate the time to full enteral nutrition when enteral and parenteral nutrition are given simultaneously.

Summary description of the invention

The present inventors have unexpectedly found that the synthetic nutritional compositions according to the invention are more rapidly emptied from the stomach, despite having a high content of LCFA relative to MCFA. In this way, the synthetic nutritional compositions of the present invention make it possible to provide the benefits of aLCFs without slowing gastric emptying.

Furthermore, the compositions according to the invention show an increased stimulation of intestinal digestive capacity, as well as of intestinal hormones [eg, fibroblast growth factor 19 (FGF-19) and cholecystokinin (CCK)].

Thus, the invention relates to synthetic nutritional compositions capable of being more rapidly evacuated from the stomach after consumption in an individual, comprising, with respect to total fat: intermediate chain fatty acids, at least 98% in the form of triglycerides, in an amount ranging from 0% to 15% by weight; at least one unsaturated fatty acid comprising oleic acid in an amount of at least 35% by weight, with respect to total fats;

palmitic acid, at least 98% as triglycerides, in an amount in the range of not more than 13%; for use in stimulating liver maturation,

and/or to reduce the risk of liver disease.

In one aspect, the individual is an infant or toddler.

In one aspect, the composition for use as mentioned above is useful to reduce the accumulation of gastric residuals, and/or to improve tolerance to enteral feeding and/or to reduce the risk of regurgitation and/or vomiting in infants or young children.

In one aspect, the composition is an infant formula, a fortifier, such as a dairy fortifier, a starter formula, a follow-on formula, a grower milk, or a supplement or adjunct.

Brief description of the figures

Figure 1 shows an overview of the study described in Example 1.

Figure 2 shows the results of the gastric emptying measurements of Example 1. The dots represent the estimated means and the bars the 95% confidence interval of the mean gastric emptying times after consumption of the different meals. M=Food (see Table 1 and Tables 2 to 6 for composition); * indicates P<0.0001; ** indicates P=0.0003. Average time (t50/min)

Figure 3 and Figure 5 show the results of FGF19 measurements in blood samples that were taken during the experiments described in Example 1. In Figure 3, the dots represent the estimated means and the bars the range of values. 95% confidence of the area under the curve of FGF19 secretion kinetics, corrected for baseline FGF19 values. M=Food (see Table 1 and Tables 2 to 6 for composition); ** indicates P=0.001. Area above baseline (AOB), (picograms/mImin). Figure 5 is a box plot of peak FGF19 levels (picograms/mL) after correction for baseline FGF19 values. * indicates meals in which Mx > MI, p < 0.05

Figure 4 and Figure 6 show the results of the measurement of bile acids in the blood samples taken during the experiment described in Example 1. In Figure 4, the points represent the estimated means and the bars, the range of values. 95% confidence of the area under the curve of bile acid secretion kinetics, corrected for baseline bile acid values. Area above baseline (AOB), (micromoles/lmin). * indicates P=0.9; ** indicates P=0.3; *** indicates P=0.0003; **** indicates P=0.0001. Figure 6 is a box plot of peak bile acid levels (micromoles/L) after correction for baseline bile acid values. * indicates meals where Mx > M I, p < 0.05.

Figures 7 and 8 show the results of the measurement of cholecystokinin (CCK) in blood samples taken during the experiment described in Example 1. Figure 7 is a box plot of the area under the CCK secretion kinetics curve, corrected for baseline bile acid values (picomoles/lmin) after correction for baseline CCK values. * indicates meals where Mx > M I, p < 0.05. Figure 8 is a box plot of peak FGF19 levels (picomoles/L) after correction for baseline CCK values. * indicates meals where Mx > MI, p < 0.05; # indicates meals where Mx < MI, p < 0.05.

Detailed description of the invention

Definitions

Before discussing the present invention in greater detail, the following terms and conventions will first be defined: The term "synthetic" means that it was obtained by chemical and/or biological means, as opposed to "natural (found in nature)", for example, not of human origin (eg, this is not breast milk).

The term "nutritional" means that it nourishes the subject. Synthetic nutritional compositions according to the invention are typically for enteral, orogastric or nasogastric feeding and may include a carbohydrate and/or protein source.

The synthetic nutritional compositions according to the invention may be intended for infants and/or young children, and may, for example, be formulated as an infant formula, a growth milk, any other milk-based nutritional composition, a supplement (or a supplement). ), a fortifier such as a dairy fortifier (eg, human dairy fortifier). The nutritional compositions can be presented in the form of powders or in liquid form.

The term "supplement" refers to a nutritional composition that typically provides the selected nutrients, even though they do not represent a significant portion of the subject's overall nutritional needs. They typically do not represent more than 0.1%, 1%, 5%, 10% or 20% of the subject's daily energy needs. The Supplements may be provided, for example, in the form of a pill, tablet or powdered supplement which may, for example, be dissolved in water or sprinkled on food. Most preferred is a powder supplement which can be dissolved in a liquid or sprinkled on food, most preferably it can be dissolved in water.

The term "complement" means the same as supplement, and the terms are used interchangeably in the present description.

The expression “infant formula” refers to a food intended for a particular nutritional use by infants during the first months of life and which by itself satisfies the nutritional requirements of this category of person (Article 2(c) of the Directive on the European Commission 91/321/Ee C 2006/141/EC of December 22, 2006 on infant formulas and follow-up formulas). It further refers to a nutritional composition intended for infants and as defined in the Codex Alimentarius (Codex STAN 72-1981) and Infant Specialties (incl. Food for Special Medical Purposes). It should be understood that infants may be fed infant formula only, or that infant formula may be used as a supplement to human milk.

Infant formulas can encompass starter infant formulas and follow-on or follow-on formulas. Generally, a starter formula is used for infants from birth as a substitute for breast milk. A follow-up or continuation formula is typically given from the sixth month onwards. This constitutes the main liquid element in the progressively diversified diet of this category of people.

The term "premature infant formula" refers to an infant formula intended for a premature infant.

The expression "growth milk" refers to that which is provided from one year of age. It is generally a milk-based beverage tailored to the specific nutritional needs of young children.

The term "fortifier" refers to a nutritional composition for infants intended to be added to or diluted with infant formula or human milk.

The nutritional composition according to the invention may be a hypoallergenic nutritional composition. The term "hypoallergenic nutritional composition" means a nutritional composition that is not likely to cause allergic reactions.

In accordance with Commission Directive 2006/141/EC of December 22, 2006 on infant formulas and follow-on formulas, article 1.2 (a) and (b), the term “infant” means children less than 12 months of age. age.

The term "toddler" refers to a child between one and three years of age, also referred to as a "one to three year old child."

The term “preterm” or “premature” refers to an infant or young child who has not been born at term. Generally, it refers to an infant or young child who was born before 37 weeks of gestational age. The terms “infant(s)/child(ren) born prematurely”, “infant(s)/toddler(s) born prematurely”, “infant(s)/child(ren) ) small premature(s), and “premature” can be used interchangeably.

A “term infant/toddler” means an infant or toddler born at term. Generally, it refers to an infant or young child who was born at or after 37 weeks of gestation.

By the term “small for gestational age” or “SGA” is meant an infant or young child who is smaller in size than normal for gestational age at birth, most commonly defined as a weight below the 10th percentile. of gestation ages. In some embodiments, the SGA condition may be associated with intrauterine growth restriction (IUGR), which refers to a condition in which a fetus is unable to reach its potential size.

By the term "low birth weight" is meant any body weight less than 2500 g at birth. Therefore, it includes:

• infant or young child who has/had a body weight at birth of 1800 to 2500 g (often referred to as “low birth weight” or BPA)

• infant or young child who has/had a body weight of 1OOO to 18OO g at birth (referred to as “very low birth weight” or Mb PAN)

• infant or young child who has/had a body weight of less than 1OOO g at birth (referred to as “extremely low birth weight” or ELBW)

Low birth weight infants or toddlers may or may not be premature, and similarly, infants or toddlers who are small for gestational age may or may not be premature.

The term "vulnerable infants and/or young children" is used in this application to refer to infants and/or young children who present or have presented developmental problems, such as infants and/or young children with at least least one of the following: with LBW, who are critically ill, who were born prematurely, small for gestational age, who experienced intrauterine growth retardation, and/or who suffer(s) from growth retardation due to disease and/or malnutrition.

The term "critically ill" refers to individuals with a life-threatening illness or injury. Such individuals, for example, an infant or young child, may require enteral, orogastric or nasogastric, intragastric, intraduodenal, or intrajejunal feeding, and may be at risk of requiring parenteral feeding.

The term "intermediate chain fatty acid" (or ICFA) refers to saturated linear aliphatic chain n-carboxylic acids, and are composed in total of 6 to 12 carbon atoms. The intermediate chain fatty acids of the present invention can be hexanoic acid (comprising 6 carbon atoms, C6:0 also called caproic acid), octanoic acid (comprising 8 carbon atoms, C8:0, also called caprylic acid) , decanoic acid (comprising 10 carbon atoms or C10:0, also called capric acid) and/or dodecanoic acid (comprising 12 carbon atoms or C12:0, also called lauric acid).

In the synthetic nutritional compositions of the invention, the medium chain fatty acids are mainly present (ie, at least 98%, such as more than 98.5%, or more than 99% or more than 99.5%). in the form of triglycerides. The expression "intermediate chain triglycerides" (or TCI) refers to intermediate chain fatty acid esters of glycerol, that is, a compound formed by a main chain of glycerol and three fatty acids. In the case of Ios TCI, two or three of the fatty acid chains linked to glycerol have an intermediate chain length In the context of the present application, the terms "triglyceride", "triacylglyceride" and "triacylglycerol" are used interchangeably and refer to the same compound.

The term "TCI oil" refers to a manufactured product comprising medium chain triglycerides.

The term "long-chain fatty acid" (or LCFA) refers to n-carboxylic acids of straight or saturated or branched (poly)unsaturated aliphatic chains, and are composed in total of more than 12 carbon atoms. Examples of long chain fatty acids include palmitic acid (comprising 16 carbon atoms, or C16:0) and oleic acid (18:1 cis-9). Similarly, the long chain fatty acids of the present invention are primarily (ie, at least 98%, such as more than 98.5%, or more than 99% or more than 99.5%) in the form of triglycerides. The term "long-chain triglycerides" (or TCI) refers to long-chain fatty acid esters of glycerol, that is, a compound formed by a main chain of glycerol and three fatty acids, where two or three chains of fatty acids linked to glycerol are long in length.

The term "long chain polyunsaturated fatty acid" (or LC-PUFA) refers to a polyunsaturated fatty acid (PUFA) having C20 or C22 carbon atoms. Polyunsaturated fatty acids (PUFA) are unsaturated fatty acids that contain more than one double bond in their main chain.

The term "sn 1,3 palmitic acid" is intended to refer to palmitic acid esterified at the sn 1,3 position.

The term "sn 2 palmitic acid" is intended to refer to palmitic acid esterified at the sn 2 position.

The term "% by weight" means percent by weight. All percentages are by weight of total fat unless otherwise indicated.

The term "prebiotic" means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or activity of healthy bacteria such as bifidobacteria in the human colon (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 125:1401-12, 1995).

The term “probiotic” means preparations of microbial cells or components of microbial cells with a beneficial effect on the health or well-being of the host (Salminen S, Ouwehand A. Benno Y. et al., “Probiotics: how should they be defined "Trends Food Science. Technol. 10107-10, 1999).

The term "consists essentially of" means that, in addition to those components which are mandatory, other components may additionally be present in the composition, provided that the essential characteristics of the composition are not materially affected by their presence.

As used in this specification, the terms "comprise", "comprising" and similar terms are not to be construed in an exclusive or exhaustive sense. In other words, they are intended to refer to "including, but not limited to".

The term "gastric residuals" refers to the food from a previous feeding that remains in the stomach at the start of the next feeding.

Synthetic nutritional compositions

The nutritional compositions of the invention show a higher rate of gastric evacuation, despite having high amounts of LCFA (see results in Example 1 and Figure 2).

Additionally, LCFA have many benefits that have been reported, which are also unexpectedly achieved with the composition of the invention. Intragastric lipase content is higher in preterm infants fed a LCFA-rich formula than in those fed a ClFA formula (Hamosh, 1991). Furthermore, contrary to SCFAs, foods rich in SCFAs do not stimulate pancreatic exocrine, bile, and cholecystokinin (CCK) secretions (Vu, 1999). Furthermore, superior mesenteric artery (SMA) blood flow is stimulated more by SCFAs than by SCFAs (Vu, 20o1). Impaired SAM blood flow is associated with enteral food intolerance in preterm infants (Fang, 2001; Robel-Tillig, 2004).

However, SCFAs are also associated with longer gastric emptying times.

Some infants suffer from immature gastrointestinal motility of the intestinal system leading to slow transit, delayed gastric emptying, and bolus accumulation in the stomach (ie, gastric residuals).

Thus, it appears that nutritional compositions based on LCFA would be contraindicated, based on the assumption that LCFA would further reduce motility, and/or further increase the accumulation of gastric residues. In fact, MCTs are widely used in conventional nutritional formulas for infants to avoid these problems.

The present invention is based on the surprising discovery that certain nutritional compositions comprising relatively high amounts of LCFA, primarily in the form of LCT, actually increase the rate of gastric emptying. Thus, the compositions of the invention provide a way to deliver the nutritional benefits of LCFA, even in individuals where the gut is compromised, eg, in vulnerable infants and/or young children; critically ill patients of any age, such as critically ill adult patients; or elderly. Any patient previously parenterally fed, partially parenterally fed, or at risk of parenteral feeding may benefit from the compositions for use according to the invention. LCFA absorption was accompanied by an increase in intestinal digestive capacity (as reflected by increased secretion of bile salts) as well as intestinal hormones (ie, cholecystokinin (CCK)). The increase in SCFA uptake was also accompanied by an increase in fibroblast growth factor 19 (FGF-19). FGF 19 is an intestinal hormone that can reduce the risk of hepatic cholestasis and steatosis, and stimulate liver growth. Intestinal FGF-19 may also exert beneficial effects on glucose metabolism by increasing insulin sensitivity and inducing glycogen synthesis. Additionally, FGF-19 can stimulate protein synthesis, leading to growth in lean body mass (Schaap, 2012; Reue, 2014).

The compositions of the invention may comprise ICFA in an amount ranging from 0% to 15% by weight, from 0% to 10% by weight, from 0% to 8% by weight, from 0% to 5% by weight. , or it can be essentially free of AGCI.

In some embodiments of the invention, the synthetic nutritional composition comprises intermediate chain fatty acids mainly in the form of triglycerides in a total amount comprised in the range of 10% to 15% by weight, with respect to total fats; such as from 10.1% to 15%, from 10.5% to 15%, from 11% to 15%, from 12% to 15%, from 13% to 15%, from 14% to 15%, or by for example, from 10.1% to 14%, from 10.5% to 14%, or from 10.5% to 13%, or from 11% to 15%, or from 12% to 15%; all percentages are by weight.

Some additional embodiments refer to a synthetic nutritional composition according to the invention, and in which:

• the hexanoic acid is in an amount comprised in the range of 0% to 1%, with respect to the total fats; such as, for example, from 0.05% to 0.5% by weight, from 0.05% to 0.4%, from 0.06% to 0.4%, or from 0.07% to 0, 3% by weight;

• octanoic acid is in an amount comprised in the range of 0% to 10%, with respect to total fats; such as, for example, from 2% to 8%, from 1.55% to 2% by weight, from 1.6% to 2%, from 1.65% to 2%, from 1.7% to 2% in weigh;

• decanoic acid is in an amount comprised in the range of 0% to 10% by weight, with respect to total fats; such as, for example, from 0% to 1.8%, from 0.1% to 1.8%, from 1% to 1.7%, from 1% to 1.5% or from 1.2% to 1.8% by weight, and

• dodecanoic acid is in an amount ranging from 0% to 12.0% by weight with respect to total fats, such as, for example, from 0% to 10%, from 0% to 8%, of 0% to 6%, from 0% to 4% or, for example, from 1% to 12%, from 2% to 12%, from 4% to 12%, from 6% to 12%, from 8% to 12 % or from 10% to 12%.

An additional embodiment refers to a synthetic nutritional composition according to the invention, comprising intermediate chain fatty acids mainly in the form of triglycerides, in a total amount comprised in the range of 10.1% to 15% by weight, such as 10 .5% to 15%, from 11% to 15%, from 12% to 15%, from 13% to 15%, from 14% to 15%, or, for example, from 10.1% to 14%, of 10.5% to 14%, or 10.5% to 13%, or 11% to 15%, or 12% to 15%, with respect to total fat, and long chain fatty acids mainly in form of triglycerides in a total amount comprised in the range of 85% to 89.9% by weight with respect to total fats, and in which:

• hexanoic acid is in an amount comprised in the range of 0% to 0.5% by weight with respect to total fats;

• octanoic acid is in an amount comprised in the range of 1.55% to 2% by weight with respect to total fats;

• decanoic acid is in an amount ranging from 1% to 1.8% by weight with respect to total fats, and

• dodecanoic acid is in an amount ranging from 8.0% to 12.0% by weight with respect to total fats.

A still further embodiment refers to a synthetic nutritional composition according to the invention, comprising intermediate chain fatty acids mainly in the form of triglycerides, in a total amount comprised in the range of 10.1% to 15% by weight, such as 10.5% to 15%, from 11% to 15%, from 12% to 15%, from 13% to 15%, from 14% to 15%, or, for example, from 10.1% to 14%, from 10.5% to 14%, or from 10.5% to 13%, or from 11% to 15%, or from 12% to 15%, with respect to total fats, and mainly long-chain fatty acids in the form of triglycerides in a total amount comprised in the range of 85% to 89.9% by weight with respect to total fats, and in which:

• hexanoic acid is in an amount comprised in the range of 0.05% to 0.5% by weight with respect to total fats;

• octanoic acid is in an amount comprised in the range of 1.55% to 2% by weight with respect to total fats;

• decanoic acid is in an amount ranging from 1% to 1.8% by weight with respect to total fats, and

• dodecanoic acid is in an amount ranging from 8.0% to 12.0% by weight with respect to total fats.

Fatty acids

The composition of the invention comprises at least one unsaturated fatty acid, mainly in the form of triglycerides, in an amount of at least 35% by weight, such as at least 38%, such as from 40% to 90%, such as from, for example, 50% to 80%, from 50% to 75%, from 50% to 70% or, for example, from 55% to 70% by weight with respect to total fats.

Examples of unsaturated fatty acids include oleic acid, as well as polyunsaturated fatty acids (PUFAs), such as linoleic acid, alpha linoleic acid, and eicosenoic acid.

The composition of the invention comprises oleic acid in an amount of at least 35%, such as at least 38%, such as from 40% to 90%, such as from, for example, 50% to 80%, of 50% to 75%, from 50% to 70% or, for example, from 55% to 70% by weight with respect to total fats.

In one embodiment, the composition comprises a long chain fatty acid in an amount between 75% and 95% by weight of total fat, for example, between 75% and 90% by weight of total fat.

Fatty acids-PUFA

In a particularly advantageous embodiment of the invention, the composition of the invention further comprises at least one polyunsaturated fatty acid (PUFA), in which the PUFA or Ios PUFA are present in an amount generally of at least 0, 1%, such as at least 8%, preferably at least 10%, with respect to the total fatty acids. Polyunsaturated fatty acids can be classified into various groups based on their chemical structure. Among those PUFAs, omega-3 and omega-6 PUFAs can be distinguished.

Omega-3 polyunsaturated fatty acids (u>-3 or n-3) include alpha linolenic acid (ALA) 18:3, stearidonic acid (SDA) 18:4, eicosatrienoic acid (ETE) 20:3, eicosatetraenoic acid n- 3 (ETA) 20:4, eicosapentaenoic acid (EPA) 20:5, n-3 docosapentaenoic acid (DPA) 22:5, and docosahexaenoic acid (DHA) 22:6. In In a particularly advantageous embodiment, the PUFAs according to the invention comprise alpha-linolenic acid, which is an essential fatty acid.

Omega-6 polyunsaturated fatty acids (u>-6 or n-6) include linoleic acid 18:2, gamma linolenic acid (GLA) 18:3, eicosadienoic acid n-620:2, dihomo gamma linolenic acid (DGLA) 20 :3, arachidonic acid (AA or ARA) 20:4, n-6 docosadienoic acid 22:2, and docosapentaenoic acid 22:5. In a particularly advantageous embodiment, the PUFAs according to the invention comprise linolenic acid, which is an essential fatty acid.

In a particularly advantageous embodiment, the composition of the invention also contains at least one PUFA, which is preferably a PUFA n-3 and/or n-6 (that is, a PUFA n-3, a PUFA n-6 or , more preferably, a mixture of PUFA n-3 and n-6), in which the PUFA are present in an amount generally of at least 0.8% by weight, preferably at least 1.0% by weight , with respect to the total fatty acids. This leads (considering that total fats comprise 90% to 96% by weight of fatty acids, see above) to an amount of at least about 0.8% by weight, preferably at least about 1.0% by weight. by weight, with respect to total fat.

The n-3 PUFA can be a C20 or C22 n-3 fatty acid. The n-3 C20 or C22 PUFA is advantageously present in an amount of at least 0.4% by weight, with respect to all the fatty acids in the composition. This leads to an amount of at least about 0.4% by weight, with respect to the total fats of the composition. Preferably, the n-3 PUFA is docosahexaenoic acid (DHA, C22:6).

The n-6 PUFA can be a C20 or C22 n-6 fatty acid. The n-6 C20 or C22 PUFA is advantageously present in an amount of at least 0.4% by weight, with respect to all the fatty acids in the composition. This leads to an amount of at least about 0.4% by weight, with respect to the total fats of the composition. Preferably, the n-6 PUFA is arachidonic acid (ARA, C20:4).

In a particularly advantageous embodiment, the PUFAs comprise at least 0.4% by weight of docosahexaneoic acid and at least 0.4% by weight of arachidonic acid, with respect to the total fatty acids.

The source of PUFA can be, for example, egg lipids, fungal oil, low EPA fish oil, or algal oil. The PUFAs of the composition of the invention can be provided in small amounts of oils containing large amounts of preformed arachidonic acid and docosahexaenoic acid, such as fish oils or microbial oils.

The presence of Ios PUFA is especially advantageous for various key health benefits, such as cognitive benefits, visual and cognitive development, anti-inflammatory properties, as is known in the art.

There are many reports in the literature suggesting that these fatty acids may be essential for the optimal development of cognitive function. Among its many functions, DHA influences the function of the blood-brain barrier, the activity of membrane-bound enzymes and ion channels, dopaminergic and serotonergic neurotransmission, and signal transduction (Yaboob, P Annu. Rev. Nutr. 2009.29 :257-282).

Fatty acids - palmitic acids

The presence of palmitic acid mainly in the form of triglycerides is especially advantageous in the event that palmitic acid is esterified in the sn-2 position of the triglycerides.

However, palmitic acid esterified at the sn-1,3 position of triglycerides is often present in high amounts in some synthetic nutritional compositions, for example, in standard infant formulas. In the event that palmitic acid Sn 1,3 is digested, free fatty acids are released which form complexes with minerals, ie soaps. These soaps are not absorbable and are lost in the feces. This leads to mineral depletion as well as poor nutrient absorption. Thus, it is desired to have lower levels of sn 1,3-palmitic acid. In the synthetic nutritional composition of the present composition, the total levels of palmitic acid sn-1,3 are reduced, in part by reducing the total amount of palmitic acid present in the compositions of the invention.

Without theoretical support, it is believed that unabsorbed palmitic acid soaps, upon reaching the ileum, may stimulate L cells to release the hormone GLP1, which is known to slow gastric emptying. Thus, reducing the amount of palmitic acid soaps may contribute to increasing the rate of gastric emptying.

The nutritional composition of the invention comprises palmitic acid, at least 98%, such as more than 98.5%, or more than 99% or more than 99.5%) in the form of triglycerides, in an amount comprised in the range of no more than 13% with respect to total fats; such as 0% to 12%, 0% to 10%, 0% to 9%, 1% to 8%, 2% to 6%, 2% to 5%, 2% to 4% , from 2% to 3.5% by weight of palmitic acid.

In some embodiments, palmitic acid is present in an amount of 2% to 5% by weight, 2% to 4% by weight, or 2.5% to 3.5% by weight based on total fat.

Some additional specific embodiments of the nutritional composition of the invention comprise no more than 7% by weight of sn 1,3 palmitic acid, with respect to total fats.

An additional embodiment refers to the nutritional composition of the invention in which palmitic acid sn-2 represents from 15% to 30% by weight of total palmitic acid and in which palmitic acid sn-1,3 represents 70%. to 75% by weight of total palmitic acid.

In some embodiments, the nutritional composition of the invention comprises sn 1,3 palmitic acid in an amount of no more than 7% by weight, with respect to total fat, such as an amount of from 0% to 7%, from 1% to 7%, from 1% to 6.5%, from 1% to 6%; or such as from 2% to 7%, from 2% to 5%, from 2% to 4% by weight or, for example, from 3% to 7%, from 4% to 7%, from 5% to 7% or from 6% to 7% by weight, with respect to total fats.

Coconut oil

Other embodiments relate to the synthetic nutritional composition according to the invention, wherein the composition comprises coconut oil in an amount ranging from 10% to 25% based on total fat.

A specific embodiment refers to a synthetic nutritional composition according to the invention comprising coconut oil in an amount ranging from 10% to 14%, from 10% to 12% by weight with respect to total fats.

Coconut oil contains a mixture of medium chain fatty acids that is similar to that found in human milk.

The formulations: mixtures of fats

A specific embodiment of the invention is that in which the nutritional composition according to the invention consists essentially of fat, and thus is a mixture of fats. Said mixture of fats is useful for preparing additional nutritional compositions, such as infant formulas, particularly infant formulas suitable for infants who are born prematurely or with low birth weight or who experienced intrauterine growth retardation or who suffered growth retardation due to disease and/or or malnutrition, and/or infants suffering from or at risk of intestinal and/or liver disease.

The fat blend may be the only source of fat in an infant formula.

formulations

In other specific embodiments, the composition according to the invention further comprises a protein source and/or a carbohydrate source.

infant formula

In advantageous embodiments of the invention, the composition according to the invention is an infant formula, in particular a formula for premature infants.

Synthetic nutritional compositions according to the invention may be, for example, an infant formula; a fortifier, such as a dairy fortifier; a start formula, a continuation formula; a growth milk; or a supplement or adjunct. The synthetic nutritional composition of the invention can be in the form of powders, liquid or concentrated liquid. The synthetic nutritional composition of the invention, e.g. eg, an infant formula, may be a milk-based nutritional composition and may be based on cow, goat, or buffalo milk. In some advantageous embodiments, the synthetic nutritional composition of the invention is an infant formula. Infant formula can be a starter formula generally for infants less than 6 months of age or a follow-on formula generally for infants or toddlers more than 6 months of age. The composition of the invention may furthermore be a growth milk, or a fortifier, such as a human milk fortifier.

According to a particularly advantageous embodiment, the synthetic nutritional composition according to the invention is especially adapted for infants or a young child or vulnerable infant, such as infants and/or young children with PBN, who are critically ill, who are born premature, who experienced delayed birth intrauterine growth and/or who suffered from growth retardation due to disease and/or malnutrition. In further embodiments, the Synthetic nutritional composition is especially adapted for infants and/or young children who were fed parenterally or who are at risk of becoming candidates for parenteral nutrition.

In a particular embodiment, the synthetic nutritional composition according to the invention is adapted for enteral administration, for example enteral, orogastric or nasogastric administration. The administration of the formula by enteral route helps stimulate intestinal maturation, and avoids the risks associated with parenteral nutrition, such as catheter-associated infections, intestinal atrophy and hepatobiliary disorders.

The amounts of all the components expressed in this description in % by weight (% by weight) with respect to total fats, reflect the amounts of some components of the fats present in the synthetic nutritional composition, which will be consumed by the infant or the little kid. For example, the composition may be a powdered infant formula that is diluted with water to give a final liquid product. The composition according to the invention can also be a concentrated liquid that is diluted with water to achieve the final liquid product. The composition of the invention can be a liquid product that is consumed directly by the infant without modification. The composition according to the invention may be a human milk fortifier which is added to human milk or diluted with human milk. In this case, the concentration of components already present in human milk (to which the human milk fortifier is added) is taken as the mean values for lactating mothers that are known or predicted from published clinical data. .

The composition according to the present invention contains a lipid source. The lipid source can be any lipid or fat that is suitable for use in infant formulas, as long as the content of ICFA and specific proportions of LCFA meet the requirements of the invention. Preferred fat sources include high oleic palm oil, high oleic sunflower oil and high oleic sunflower oil. In addition, essential fatty acids linoleic acid and α-linolenic acid can be added. In the composition, the fat source (including optional LC-PUFAs such as ARA and/or DHA) preferably has a ratio of n-6 to n-3 fatty acids of from about 1:2 to about 10:1, preferably from about 5:1 to about 10:1, still more preferably about 7:1 to about 9:1.

The composition according to the invention is preferably such that the fats consist essentially of a mixture of 0% to 20% milk fats; 10% to 15% coconut oil; from 10% to 40% canola oil; from 10% to 25% sunflower oil; 10% to 30% high oleic sunflower oil; from 2% to 10% palmitic acid mainly in the form of triglycerides; and 1.5% to 2.5% of a mixture of ARA and DHA polyunsaturated fatty acids (such as a 1:1 mixture of ARASCO® and DHASCO® from Martek), preferably in an ARA:DHA ratio of about 1:1, with respect to total fats.

Milk fat could be efficiently replaced by Betapol®, or by AAK/Enzymotec's Infat®.

Each of these fat sources is a refined oil suitable for infant nutrition applications.

Other standard ingredients that are known to those skilled in the art for the formulation of an infant formula, human milk fortifier or growth milk may also be present in the compositions of the invention.

In this way, the composition of the invention may contain other ingredients that may act to enforce the technical effect of the components, particularly in accordance with Commission Directive n0 2006/141/EC of December 22, 2006 on infant formulas and continuation formulas.

The composition according to the present invention may additionally contain a source of carbohydrates, preferably as prebiotics, or in addition to prebiotics. Any carbohydrate source conventionally present in infant formula can be used, such as lactose, sucrose, maltodextrin, starch and mixtures thereof, although the preferred carbohydrate source is lactose.

The prebiotics that can be used according to the present invention are not particularly limited and include all food substances that stimulate the growth of probiotics or health-promoting microorganisms in the intestines. Preferably, they may be selected from the group consisting of oligosaccharides, optionally containing fructose, galactose and mannose; dietary fibers, particularly soluble fibers, soy fibers; inulin; or mixtures thereof. Some examples of prebiotics are fructooligosaccharides (FOS), galactooligosaccharides (GOS), isomaltooligosaccharides (OMI), xylooligosaccharides (XOS), arabinoxylooligosaccharides (AXOS), mannan oligosaccharides (MOS), inulin, polydextrose, soy oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinous oligosaccharides (PAO), maltooligosaccharides, gums and/or hydrolysates thereof, pectins and/or hydrolysates thereof. In a particular embodiment, the prebiotics can be fructooligosaccharides and/or inulin. In a specific embodiment, the prebiotics are a combination of f Os and inulin, such as in the product marketed by BENEO-Orafti under the trademark Orafti® oligofructose (formerly Raftilose®) or in the product marketed by BENEO-Orafti under the trademark commercial Orafti® inulin (previously Raftiline®). Another example is a combination of 70% short-chain fructooligosaccharides and 30% inulin, which is registered by Nestlé under the trademark “Prebio 1”.

In one embodiment, the synthetic nutritional composition according to the invention does not comprise any prebiotic oligosaccharides.

The prebiotics can further be a BMO (bovine milk oligosaccharide) and/or an HMO (human milk oligosaccharide) such as N-acetylated oligosaccharides, sialylated oligosaccharides, fucosylated oligosaccharides and any mixtures thereof.

A particular example of a prebiotic is a mixture of one or more galactooligosaccharides, one or more N-acetylated oligosaccharides, and one or more sialylated oligosaccharides in which the N-acetylated oligosaccharide(s) represent 0.5% to 4.0% of the the oligosaccharide mixture, the galactooligosaccharide(s) represent 92.0% to 98.5% of the oligosaccharide mixture and the sialylated oligosaccharide(s) represent 1.0% to 4.0% of the oligosaccharide mixture. Said mixture is hereinafter referred to as "CMOS-GOS". For example, a composition for use according to the invention contains from 2.5% to 15.0% by weight of CMOS-GOS on dry matter with the proviso that the composition comprises at least 0.02% by weight of a N-acetylated oligosaccharide, at least 2.0% by weight of a galacto-oligosaccharide and at least 0.04% by weight of a sialylated oligosaccharide. Documents #W02006087391 and #W02012160080 provide some examples of CMOS-GOS production.

In particular, human milk oligosaccharides, eg sialylated oligosaccharides, described in WO2012/069416 published May 31, 2012 may be included in the composition according to the invention.

Probiotics can be added to the composition according to the invention. All probiotic microorganisms can be additionally added. Preferably, the probiotic may be selected for this purpose from the group consisting of Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, Kluyveromyces, Saccharoymces, Candida, in particular selected from the group consisting of Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus salivarius, Lactobacillus lactis, Lactobacillus rhamnosus, Lactobacillus Johnsonii, Lactobacillus plantarum, Lactobacillus salivarius, Lactococcus lactis, Enterococcus faecium, Saccharomyces cerevisiae, Saccharomyces boi Some suitable examples of probiotics are selected from the group consisting of Bifidobacterium longum NCC3001 (At CC BAA-999), Bifidobacterium longum NCC2705 (CNCM 1-2618), Bifidobacterium longum NCC490 (CNCM 1-2170), Bifidobacterium lactis NCC2818 (CNCM 1-2170). 3446), Lactobacillus paracasei NCC2461 (CNCM 1-2116), Lactobacillus Johnsonii NCC533 (CNCM 1-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CGMCC 1.3724), Enterococcus faecium SF 68 (NCC2768); NC1|M5b) 104|M , and mixtures thereof.

The composition according to the invention may also contain a protein source. The type of protein is not considered crucial for the present invention provided that the minimum essential amino acid content requirements are met and satisfactory growth is ensured. Thus, protein sources based on whey, casein, and mixtures thereof can also be used as soy-based protein sources. As far as whey proteins are concerned, the protein source may be based on sour whey or sweet whey or mixtures thereof, and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions. Proteins can be at least partially hydrolyzed in order to increase oral tolerance to allergens, especially food allergens. In that case the composition is a hypoallergenic composition.

In a preferred embodiment, the composition may be an infant formula based on cow's milk whey. The formula may also be a hypoallergenic (HA) formula in which the cow's milk proteins are (partially or extensively) hydrolyzed. The formula can also be based on soy milk or a non-allergenic formula, for example, one based on free amino acids.

The composition of the invention may also contain all the vitamins and minerals, and other micronutrients, which are understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in the form of a salt. The presence and amounts of specific minerals and other vitamins will vary depending on the target population.

If necessary, the composition of the invention may contain emulsifiers and stabilizers such as soybeans, lecithin, citric acid esters of monoglycerides and diglycerides, and the like.

The composition of the invention may also contain other substances that may have a beneficial effect, such as lactoferrin, nucleotides, nucleosides, gangliosides, polyamines and the like.

The preparation of the composition according to the invention will be described below by way of example.

The formula can be prepared in any suitable way. For example, it can be prepared by mixing together a protein source, a carbohydrate source, and a fat source, eg, a lipid blend according to the invention including LCFA and LCFA in appropriate proportions. If used, emulsifiers can be included at this point. Vitamins and minerals can be added at this point, although they are usually added later to avoid thermal degradation. Lipophilic vitamins, emulsifiers and the like may be dissolved in the fat source prior to blending. Water, preferably water that has been subjected to reverse osmosis, can then be mixed to form a liquid mixture. The temperature of the water is conveniently in the range of about 50°C to about 80°C to aid in dispersion of the ingredients. Commercially available blenders can be used to form the liquid mix. The liquid mixture is then homogenized in two stages, for example.

The liquid mixture can then be heat treated to reduce bacterial load by rapidly heating the liquid mixture to a temperature in the range of from about 80°C to about 150°C for a period of from about 5 seconds to about 5 minutes, for example. This can be done by means of steam injection, an autoclave or a heat exchanger, eg a plate heat exchanger.

The liquid mixture can then be cooled to a temperature between about 60°C and about 85°C, for example by flash cooling. The liquid mixture can then be homogenized again, for example, in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage. The homogenized mixture can then be further cooled to add any heat sensitive components, such as vitamins and minerals. The pH and solids content of the homogenized mixture are conveniently adjusted at this point.

The homogenized mixture is then transferred to a suitable drying apparatus, such as a spray dryer or freeze dryer, and converted into powders. The powders should have a moisture content of less than about 5% by weight. Some of the carbohydrates may be added at this stage by dry blending together with one or more optional probiotic bacterial strains, or by blending them as crystal syrup together with the optional probiotic bacterial strain(s) and drying. by spraying (or lyophilization).

In the event that a liquid composition is preferred, the homogenized mixture may be sterilized and then aseptically filled into suitable containers or may first be filled into the containers and then sterilized.

In another embodiment, the composition of the invention may be a supplement in an amount sufficient to achieve the desired effect in an infant. Such a form of administration is usually more suitable for premature infants.

The amount of ICFA and LCFA for inclusion in the supplement will be selected based on the manner in which the supplement is to be administered.

The supplement may be in the form of powders, tablets, capsules, lozenges, or a liquid, for example, provided that a suitable nutritional composition for the infant results. The supplement may further contain protective hydrocolloids (such as gums, proteins and modified starches), binders, film-forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizers (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flow agents, taste-masking agents, bulking agents, gelling agents and gel-forming agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, lignin sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, agents flavorings, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.

The supplement may be added in a product acceptable to the consumer (which is an infant), such as an ingestible carrier or vehicle, respectively. Examples of such vehicles or carriers are a pharmaceutical or food composition. Examples of such compositions are infant formulas, including premature infant formulas.

In addition, the supplement may contain an organic or inorganic carrier material suitable for enteral or parenteral administration, as well as vitamins, minerals, trace elements and other micronutrients in accordance with the recommendations of government agencies, such as the European Commission Directive n0 2006/141/EC on December 22, 2006 on infant formulas and follow-up formulas.

Other formulations

The synthetic nutritional composition of the invention is discussed primarily in the context of an infant formula. However, the nutritional composition can be formulated to suit other groups, such as adults, critically ill patients, elderly patients (60 years and older), and/or patients who are at risk of parenteral nutrition or who have been parenterally fed. Such nutritional compositions may comprise components such as those discussed above in the context of infant formulas. However, synthetic nutritional compositions of the invention that are not intended for administration to infants and/or young children are not required to meet the guidelines for infant formulas.

Objective group

The invention relates to the synthetic nutritional composition according to the invention for use in administration to an individual.

In some embodiments, the synthetic nutritional composition of the invention may be advantageously administered to infants or young children. In a particular embodiment, it is used for infants younger than 12 months, younger than 6 months, or younger than 3 months or less. In a particular embodiment, the composition is an infant formula for premature infants.

In one embodiment, the synthetic nutritional composition is for use according to the invention in an individual.

In advantageous embodiments, the synthetic nutritional composition is for use according to the invention in an infant and/or young child, in particular a vulnerable infant and/or young child, such as an infant and/or young child of low body weight ( BPC), who is critically ill, premature, small for gestational age, has experienced intrauterine growth retardation, and/or is (or has been) growth retarded due to disease and/or malnutrition.

In further embodiments, the individual is a child, an adult, and/or an elderly person.

In still further embodiments, the individual may be a critically ill patient, in particular a patient who has developed or is at risk of developing a food intolerance; for example, a child, an adult and/or an elderly person who is critically ill.

In one embodiment of the invention, the composition of the invention is an infant formula intended and/or specially designed for premature infants.

In one embodiment, the synthetic nutritional composition of the invention is designed for consumption by infants between birth and one year of age. In some embodiments, it is specifically designed to meet the nutritional needs of premature infants.

In one embodiment, the synthetic nutritional composition of the invention is designed for consumption by infants or young children who have reduced intestinal motility, which may be, for example, due to immaturity of the intestine. For example, premature infants may suffer from intestinal immaturity and reduced intestinal motility.

In one embodiment, the synthetic nutritional composition of the invention is intended for consumption by infants or young children who have poor liver health or who are at risk of developing liver disease. In particular, PBN (and especially PEBN) infants often have liver disease, and thus in one particular embodiment, refers to a synthetic nutritional composition designed for such infants.

In some embodiments of the invention, the synthetic nutritional composition is for use in infants or young children who are ill. In some embodiments, it may be used in infants or young children who are critically ill, ie, with a life-threatening illness or injury.

In certain embodiments, the synthetic nutritional composition according to the invention is adapted for oral administration. In other embodiments, the composition according to the invention is adapted for intragastric (eg, orogastric, nasogastric), intraduodenal, or intrajejunal administration.

The composition can be administered (or supplied) at an age and for a period depending on the needs.

For example, the composition can be administered immediately after the birth of the infants. The composition of the invention can also be administered during the first week of the infant's life, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first month of life, or during the first 2 months of life. or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first year of life, or during the first two years of life or even longer. In some other embodiments, the composition of the invention is administered a few days, or a few weeks, or a few months after birth.

In one embodiment, the composition of the invention is provided to the infant or young child in the form of a supplemental composition to breast milk. In one embodiment, the composition is provided to the infant or young child as the sole or primary nutritional composition for at least a period of time, e.g. eg, after the 1st, 2nd or 4th month, for at least 1,2, 4 or 6 months. In some embodiments, the infant or young child receives breast milk for at least the first 2 weeks, the first 1, 2, 4, or 6 months. In one embodiment, the composition of the invention is provided to the infant or young child after said period of maternal nutrition, or is provided in conjunction with said period of breast milk nutrition.

not infants

In some other embodiments of the present invention, the synthetic nutritional compositions of the present invention are intended for patients regardless of age, especially critically ill patients regardless of age, particularly patients who have developed or are at risk of of developing food intolerance, for example, critically ill patients who have been fed by the enteral route and/or who are at risk of being fed by the enteral route. In specific embodiments, the invention relates to adults, especially critically ill adults. Adults are defined as individuals 13 years of age or older. Other specific embodiments relate to children, especially critically ill children. Children are defined as individuals over the age of 3 and under the age of 13. Some additional specific embodiments relate to elderly people, especially elderly people who are critically ill and/or are food intolerant. An elderly person is defined as 60 years of age or older.

Uses of nutritional composition

FGF-19 (fibroblast growth factor 19) is an intestinal hormone that can reduce the risk of hepatic steatosis and cholestasis and stimulate liver growth. Intestinal FGF19 may also exert beneficial effects on glucose metabolism by increasing insulin sensitivity and inducing glycogen synthesis. Said hormone can also promote protein synthesis, and lead to the growth of lean body mass (Schaap, 2012; Reue, 20l4).

The invention relates to the composition according to the invention for use in stimulating liver maturation and/or in reducing the risk of liver disease. Young children and premature and critically ill infants suffer from enteral feeding intolerance. Food intolerance prompts the health care provider to discontinue enteral feeding and to provide nutrition through parenteral nutrition.

In this way, the present invention refers to a synthetic nutritional composition according to claim 1 in the reduction of the accumulation of gastric residues, and/or the improvement of the tolerance to enteric foods, and/or for the reduction of the risk of regurgitation and/or vomiting in infants or young children, particularly in vulnerable infants and/or young children, such as infants and/or young children with bPn, and/or who are critically ill, and/or who were born prematurely and/or or who experienced intrauterine growth retardation and/or who suffered from growth retardation due to disease and/or malnutrition, and/or who were parenterally and/or orally fed who had been parenterally fed and/or at risk of become candidates for parenteral nutrition. Some specific embodiments relate to the nutritional composition for use according to the invention, where the use is in premature infants, even more specifically in LBW infants. In one embodiment, the infant or toddler may be critically ill.

Premature infants are at increased risk for insulin resistance, hyperglycemia, nutrient misuse, impaired growth in lean body mass, visceral fat accumulation, and metabolic disease later in life.

Liver function is immature in preterm infants, and liver dysfunction is common in preterm infants, affecting up to 50% of extremely low birth weight (ELBW) infants.

Thus, the invention relates to a synthetic nutritional composition according to the invention that is used to stimulate and/or ensure liver maturation or to reduce the risk of liver disease in an infant or young child, such as infants and/or children infants who are LBW, who are critically ill, who have been born prematurely, who have experienced intrauterine growth retardation, and/or who have suffered from birth retardation growth due to illness and/or malnutrition, who have been enterally fed or are at risk of becoming candidates for enteral feeding. In a particular embodiment, the synthetic nutritional composition according to the invention is intended for use in premature infants, even more specifically in LBW premature infants.

not infants

Other groups of patients may also suffer from reduced gastric motility and/or decreased absorptive capacity of the intestine and thus may benefit from the use of the inventors' synthetic nutritional composition. Examples include critically ill patients and elderly patients.

Any reference to prior art documents in this specification should not be taken as an admission that such prior art is widely known or forms part of common general knowledge in the field.

It should be noted that the embodiments and features indicated in the context of one of the aspects of the present invention also apply to the other aspects of the invention. In particular, it should be noted that the embodiments and features described in the context of infants and young children may also apply to other groups, such as adults, children, the elderly, and/or critically ill patients.

examples

Example 1

A crossover study was designed in which each subject received all test meals. Subjects were randomly assigned to one of 10 possible randomized sequences of the 5 test products. Each subject received the 5 study products during 5 different visits, separated by a minimum of 1 week washout and a maximum of 4 weeks. Each visit was spread over two days (D-1 and DO):

• Day -1 to get standardized meals

• Day O for:

^or baseline plasma sample

^o Study product intake

^o Plasma samples: breath samples

Subjects were healthy men aged 20 to 40 years with a BMI of 19 to 24.9 kg m-2 and normal fasting blood glucose.

Study Description

All five products in the study contained the same amount of maltodextrins and whey protein, but differed in their fatty acid composition. All study products contained one-third of each subject's daily energy needs, as determined by the Harris Benedict equation multiplied by a factor of 1.5 to include physical activity.

1. Maltodextrin (43% TEI)+whey protein (WP, 12% TEI)

2. Maltodextrin (43% TEI)+WP (12% TEI)+MUFA (39% TEI)+PUFA (6% TEI)

3. Maltodextrin (43% TEI)+WP (12% TEI)+MUFA (27% TEI)+MCT (12% TEI)+PUFA (6% TEI)

4. Maltodextrin (43% TEI)+WP (12% TEI)+MUFA (12% TEI)+MCT (27% TEI)+PUFA (6% TEI)

5. Maltodextrin (43% TEI)+WP (12% TEI) MCT(39% TEI)+PUFA (6% TEI).

(TEI=Total Energy Intake; WP=Whey Protein; MUFA=Monounsaturated Fatty Acids; PUFA=Polyunsaturated Fatty Acids; MCT=Medium Chain Triglycerides) See also Table 1 for meal composition.

100 mg of 13C-octanoate (Eurisotope, St. Aubin, France) was added to each study product to monitor gastric emptying.

Table 1: Fatty acid profile of study products

Meals were isocaloric for each subject, except for MI, which is the fat-free reference diet and has carbohydrate and protein contents similar to the other meals, albeit without lipids. All other meals a third of the daily energy needs of each subject, in M2 and M3 are dominated by oleic acid; in M4 and M5 by MCT.

Table 1

Table 2: composition of Meal 1 (M I)

Table 3: composition of Meal 2 (M2)

(continuation)

Table 4: composition of Meal 3 (M3)

Table 5: composition of Meal 4 (M4)

(continuation)

Table 6: composition of Meal 5 (M5)

Study

On the day of kinetics, the participants came fasting. There were no other dietary restrictions.

The drink was served at room temperature in an opaque glass with a cover to be consumed orally within 5 to 10 minutes.

Blood samples were drawn at time points beginning 1 hour before beverage intake and throughout the 4 hours of the study (see Figure 1 for an overview of the study).

gastric evacuation

Briefly, 100 mg of 13C-octanoate was dissolved in the test meals the night before the test in order to ensure complete homogeneous dissolution of the tracer. On the day of the metabolic investigation, baseline breath samples were collected into 3 glass Vacutainers at times -30 and -15 min prior to meal ingestion. All test meals were eaten in less than 10 minutes and time zero was defined as the end of food intake. Breath samples were collected at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes using the Easy Sampler Device and crimpable tubes from QuinTron (Milwaukee, Wisconsin, USA)

13C02 breath samples were analyzed for 13C enrichment using an isotope ratio mass spectrometer device (IRMS, Delta V Advantage, Thermo, Bremen, Germany) connected to a gas chromatography system (g C Trace, Thermo, Bremen, Germany). Analyzes were performed to assess the 13C02/12C02 ratio (expressed as 613C, °%o). The CO2 standard gas was calibrated against an international standard while expressing the 13C/12C ratio relative to Vienna Pee Dee Belemnite (VPDB).

The data was transformed by using nonlinear equations according to Ghoos et al. (2) by using R software to calculate the nonlinear fit of the curve. The parameter T50Meas is derived from these equations and represents the time in minutes in which half the contents of the stomach have been evacuated.

Figure 2 shows the results of T50Meas for the different meals studied. As expected, the fastest food emptied from the stomach was MI, since it did not contain any fat. It was interesting that within the meals containing fat, M2 and M3, that is, those meals that have low or no content of MCT, presented a faster gastric evacuation than m 4 and M5.

FGF-19.

FGF-19 (fibroblast growth factor 19) is an intestinal hormone that can reduce the risk of hepatic steatosis and cholestasis and stimulate liver growth. This hormone can also exert beneficial effects on glucose metabolism by increasing insulin sensitivity and inducing glycogen synthesis. Additionally, FGF-19 can stimulate protein synthesis, leading to growth in lean body mass (Schaap, 2012; Reue, 2014).

FGF19 was measured by ELISA, using a commercial kit from R&D Systems.

The results showed that FGF-19 was more stimulated in M3 and M2, ie those meals that had low or no content of MCT oil induced significantly higher levels of FGF-19 compared to the control. Meals M4 and M5 were not significantly different from control.

See also figures 3 and 5.

CCK and bile acids

Cholecystokinin (CCK) is a key intestinal hormone for the digestive process, since it induces the secretion of bile acids and pancreatic enzymes necessary for the digestion of a meal. This hormone also apparently stimulates the maturation of the exocrine pancreas.

CCK was measured by RIA, using a commercial kit from Ray Biotech. Total bile acids were measured by colorimetric enzyme assay, using a commercial kit from Bio Supply.

The results showed that CCK was more stimulated in M3 and M2, that is, those meals that had low or no content of MCT oil induced significantly higher levels of CCK than the control. In contrast, meals M4 and M5 induced less CCK secretion than the control. Therefore, bile acid levels were also significantly increased with meals M2 and M3 alone. See also figures 4, 6 and 7, 8.

cremation experiments

Experiments were performed to validate the gastric evacuation method.

Method: Samples of each test product (M1-M5) were mixed in equal proportion with simulated gastric juice, consisting of 2 mg/ml NaCl and 4.5 mg/ml pepsin at 37°C and pH 1 ,9. The physical distribution of the fats of each mixture was evaluated by measuring the optical turbidity as a function of the height of the sample (every 30 pm) over time at 37°C using a Turbisca™ lA b .

The results are presented below, in Table 7. Meal 3 was diluted to check its stability (Meal 3 (-10%)).

Table 7: In Vitro Food Coagulation Assay Results

Conclusions: Meals 2 and 5 did not show phase separation. Meals 3 and 4 showed modest cremation, which was due to aggregation of fat particles. Such separation in the stomach will be relatively minor and will have only a modest effect on gastric emptying. No effect on gastric emptying is anticipated for Meals 2, 4 and 5.

Example 2A:

Table 8: Example of a lipid mixture according to the invention

Example 2B:

Table 9: Example of a lipid mixture according to the invention

Example 3:

an example of the composition of an infant formula according to the invention is given in Table 11 below.

Table 11: example of an infant formula according to the invention

Claims (5)

r e iv in d ic a tio n s i. Synthetic nutritional composition that can be more rapidly evacuated from the stomach after consumption in an individual, comprising, with respect to total fat: - intermediate chain fatty acids, at least 98% in the form of triglycerides, in an amount ranging from 0% to 15% by weight, - at least one unsaturated fatty acid comprising oleic acid in an amount of at least 35% by weight, with respect to total fat, - palmitic acid, at least 98% in the form of triglycerides, in an amount within the range of not more than 13%, for use in stimulating liver maturation and/or for reducing the risk of liver disease. 2. The composition for use according to claim 1, wherein the individual is an infant or young child. 3. Composition for the use according to any of the preceding claims in reducing the accumulation of gastric residues, and/or for improving tolerance to enteral feeding and/or for reducing the risk of regurgitation and/or vomiting in infants or young children. 4. Composition for use according to any of claims 1 to 3, further comprising a protein source and/or a carbohydrate source. A composition for use according to claim 4, wherein the composition is an infant formula, a fortifier, such as a milk fortifier, a starter formula, a follow-on formula, a grower milk, or a supplement or adjunct.